Extinction is thought to be deficient in anxiety disorders such as PTSD, and there is a pressing need to translate animal findings in this area to humans. This five-year project represents the continuation of a close collaboration between two sites, one investigating fear extinction in rats (PI: Quirk, Univ. Puerto Rico), and the other in humans (Co-PI: Pitman, MGH-Harvard). Our main goal is to identify homologous structures in the rat and human prefrontal cortex that regulate fear and predict extinction, and to investigate these areas in PTSD. The prelimbic and infralimbic areas in rat prefrontal cortex impair and facilitate recall of extinction, respectively. In the human, the dACC and vmPFC serve similar functions to rat PL and IL, respectively. Our overarching hypothesis is that an imbalance in the activity of these prefrontal areas leads to extinction failure and PTSD. We will investigate these areas in rats and humans in four Specific Aims: 1) To investigate the activity and functional connectivity of rat prelimbic and infralimbic cortex prior to and following extinction of fear conditioning (using multichannel unit recording), and to identify neurobiological markers of extinction failure;2.) To facilitate extinction recall in rats by manipulating this prefrontal network pharmacologically;3) To investigate human homologues dACC and vmPFC in the acquisition and extinction of conditioned fear, and to identify neurobiological markers for extinction failure within these brain regions using PET-FDG and fMRI imaging in healthy humans;4) To characterize the activity of the dACC and vmPFC in PTSD patients and to determine whether neurobiological markers for extinction failure are present in this disorder. We predict that the PL/IL ratio of resting activity in rats, or dACC/vmPFC ratio of resting activity in healthy humans, will be inversely correlated with extinction. In PTSD, we predict that the dACC/vmPFC ratio will be increased and will be correlated with extinction failure. Moreover, we predict hypoactive vmPFC and hyperactive dACC in PTSD patients during extinction retention tests. Exposure therapies that are commonly used to treat anxiety disorders are based on extinction. In addition to elucidating the pathophysiology of PTSD, identifying neurobiological markers of extinction failure could become a screening tool for persons at high risk of trauma exposure. Identifying neurobiological interventions that improve extinction retention could lead to novel treatments for anxiety disorders, mood disorders, and addictions. PUBLIC HEALTH RELEVANCE: Approximately 13% of the adult population in the U.S. suffer from an anxiety disorder, in which it is difficult to control or extinguish fear responses. This proposal will translate findings on the brain mechanisms of extinction from rats to humans, using neuronal recording and functional brain imaging, in order to identify neurobiological markers of extinction success or failure. If successful, this approach could lead to a screening tool for identifying persons at high risk for developing an anxiety disorder and could augment existing extinction-based therapies.